Although health disparities between racial and ethnic populations have been acknowledged for a variety of systemic diseases, minority health also has been negatively impacted by genetic disorders that are prevalent among minority groups. Sickle cell disease (SCD) is a devastating genetic disorder worldwide. SCD is also associated with serious complications such as stroke and hypertension. Hydroxyurea (HU) was introduced for the treatment of this disorder with the morbidity and mortality of SCD patients significantly improving, which is attributable at least in part to an increased production of fetal hemoglobin (Hb F) by HU. However, one third to half of SCD patients are resistant to this chemical and they demonstrate no significant increase in Hb F levels. The mechanisms of action of HU as well as those underlying resistance to HU therapy still remain unclear. The long-term goal of this proposal is to improve health conditions of African-Americans by developing novel HU-based combination therapies for SCD patients. In this proposal, we will test the hypothesis that HU-induced Hb F expression is enhanced by combining a cAMP-dependent phosphodiesterase inhibitor. In Specific Aim 1, we will determine intracellular signaling pathways that play a critical role in HU-induced Hb F expression. Using CD34+-derived primary erythroid cells, we will examine whether HU modulates the activities of intracellular signaling pathways that have been shown to be involved in Hb F expression. Specific Aim 2 is to determine whether HU-induced Hb F expression is further increased by combining a cAMP-dependent PDE inhibitor. Here we will utilize SCD model mice, which exclusively express human globins including beta S globin. SCD mice will allow us to confirm the role of cAMP signaling pathways in Hb F expression as well as to provide an experimental arena to develop novel HU-based combination therapies for SCD patients. If successfully implemented, this proposal will enhance our understanding of mechanisms that regulate the expression of the g-globin genes during development and provide important information to develop novel Hb F inducers for treating beta-globin disorders, which are also common to minority populations.